Pharmacological Inhibition of Spermine Oxidase Suppresses Excitotoxicity Induced Neuroinflammation in Mouse Retina.
Animals
Antioxidants
/ metabolism
Diabetic Retinopathy
/ drug therapy
Disease Models, Animal
Male
Mice
Mice, Inbred C57BL
Neurodegenerative Diseases
/ drug therapy
Neuroinflammatory Diseases
/ drug therapy
Oxidation-Reduction
/ drug effects
Oxidoreductases Acting on CH-NH Group Donors
/ antagonists & inhibitors
Putrescine
/ analogs & derivatives
Retina
/ diagnostic imaging
Signal Transduction
/ drug effects
Polyamine Oxidase
acrolein
antioxidant signaling
microglia
neuroinflammation
oxidative damage
polyamine oxidation
spermine oxidase
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
15 Feb 2022
15 Feb 2022
Historique:
received:
10
01
2022
revised:
10
02
2022
accepted:
11
02
2022
entrez:
26
2
2022
pubmed:
27
2
2022
medline:
19
3
2022
Statut:
epublish
Résumé
Polyamine oxidation plays a major role in neurodegenerative diseases. Previous studies from our laboratory demonstrated that spermine oxidase (SMOX, a member of the polyamine oxidase family) inhibition using MDL 72527 reduced neurodegeneration in models of retinal excitotoxicity and diabetic retinopathy. However, the mechanisms behind the neuroprotection offered by SMOX inhibition are not completely studied. Utilizing the experimental model of retinal excitotoxicity, the present study determined the impact of SMOX blockade in retinal neuroinflammation. Our results demonstrated upregulation in the number of cells positive for Iba-1 (ionized calcium-binding adaptor molecule 1), CD (Cluster Differentiation) 68, and CD16/32 in excitotoxicity-induced retinas, while MDL 72527 treatment reduced these changes, along with increases in the number of cells positive for Arginase1 and CD206. When retinal excitotoxicity upregulated several pro-inflammatory genes, MDL 72527 treatment reduced many of them and increased anti-inflammatory genes. Furthermore, SMOX inhibition upregulated antioxidant signaling (indicated by elevated Nrf2 and HO-1 levels) and reduced protein-conjugated acrolein in excitotoxic retinas. In vitro studies using C8-B4 cells showed changes in cellular morphology and increased reactive oxygen species formation in response to acrolein (a product of SMOX activity) treatment. Overall, our findings indicate that the inhibition SMOX pathway reduced neuroinflammation and upregulated antioxidant signaling in the retina.
Identifiants
pubmed: 35216248
pii: ijms23042133
doi: 10.3390/ijms23042133
pmc: PMC8875684
pii:
doi:
Substances chimiques
Antioxidants
0
MDL 72527
1YVR349GN4
Oxidoreductases Acting on CH-NH Group Donors
EC 1.5.-
Putrescine
V10TVZ52E4
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NEI NIH HHS
ID : P30 EY031631
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY028569
Pays : United States
Organisme : University of Georgia
ID : Start up funds
Organisme : NEI NIH HHS
ID : R01EY028569
Pays : United States
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